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Insulin-like Growth Factor-1 Improves Survival in Sepsis via Enhanced Hepatic Bacterial Clearance

¹ Division of Pulmonary and Critical Care and Occupational Medicine, Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa; and ² Department of Internal Medicine, Iowa City Department of Veterans Affairs Medical Center, Iowa City, Iowa

Correspondence and requests for reprints should be addressed to Alix Ashare, M.D., Division of Pulmonary, Critical Care, and Occupational Medicine, University of Iowa College of Medicine, 200 Hawkins Drive, C-33 GH, Iowa City, IA 52242. E-mail: alix-ashare{at}uiowa.edu

Rationale: Both insulin-like growth factor (IGF)-1 and bacterial clearance by Kupffer cells are significantly reduced in severe sepsis. Kupffer cell apoptosis is triggered by tumor necrosis factor (TNF)- and activation of the PI-3 kinase pathway prevents TNF-induced Kupffer cell death.

Objectives: We evaluated if the marked decline in IGF-1 is related to bacterial clearance in sepsis.

Methods: Sepsis was induced in C57BL/6 mice by intratracheal inoculation with Pseudomonas aeruginosa (strain PA103). Some mice received IGF-1 24 mg/kg either before infection or 12 hours after infection. In vitro studies were performed using the clonal Kupffer cell line KC13-2.

Measurements and Main Results: Sepsis resulted in decreased levels of IGF-1. In vitro studies with KC13-2 cells demonstrated that IGF-1 protected Kupffer cells against TNF-–induced apoptosis by activating the PI-3 kinase pathway and stabilizing the inhibitor of apoptosis protein, XIAP. In the animal model, pretreatment with IGF-1 decreased hepatic TNF- and IL-6, improved hepatic bacterial clearance as demonstrated by real-time polymerase chain reaction with primers specific for P. aeruginosa, and improved survival in severe sepsis. Moreover, we rescued mice from severe sepsis by IGF-1 treatment 12 hours after infection.

Conclusions: These studies show that the decline in IGF-1 levels in sepsis is related to bacterial clearance and that replacement of IGF-1 in a murine model of sepsis improves overall survival.

Key Words: bacteria • macrophage • infection • apoptosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Severe sepsis results in organ dysfunction and high risk of mortality. Liver dysfunction in sepsis can cause a loss of hepatic bacterial clearance, which contributes to poor outcome. What This Study Adds to the Field IGF-1 therapy improves Kupffer cell survival, thereby enhancing bacterial clearance and improving survival in a murine model of sepsis.